Now approved for adults with major depressive disorder (adjunctive)

For major depressive disorder (Adjunctive) in adultsAdding CAPLYTA demonstrated superior depression symptom relief in MDD patients with or without symptoms of anxiety* compared to an antidepressant alone1,2

Change from baseline in MADRS total score at 6 weeks1,2
This graph illustrates the LSM change from baseline for patients receiving CAPLYTA 42 mg or placebo.This graph illustrates the LSM change from baseline for patients receiving CAPLYTA 42 mg or placebo.

~15-point, clinically meaningful and significant improvement in depressive symptoms2

MDD patients with or without symptoms of anxiety* were included in the study2

All patients had moderate or severe depression at baseline and
CAPLYTA + ADT separated from ADT alone in 1 week2

Weekly time points prior to 6 weeks were not powered for statistical comparison and are descriptive only.

*CAPLYTA is not approved for the treatment of anxiety disorders. Symptoms of anxiety in patients with MDD are based on DSM-5 criteria for anxious distress.

Secondary endpoints:

  • 46% and 40% of CAPLYTA-treated patients achieved response at 6 weeks (defined as MADRS Total Score ≥50% reduction from baseline) in Studies 501 and 502, respectively2
  • 26% and 25% of patients achieved remission at 6 weeks (defined as MADRS total score ≤10) in Studies 501 and 502, respectively2

Limitation: These secondary endpoints were not powered for statistical comparison and are descriptive only; results require cautious interpretation.

ADT=antidepressant therapy; DSM=Diagnostic and Statistical Manual of Mental Disorders; LSM=least squares mean; MADRS=Montgomery-Åsberg Depression Rating Scale; MDD=major depressive disorder; PHQ-9=Patient Health Questionnaire-9.

Pivotal adjunctive MDD studies: Pooled study design and baseline characteristics

CAPLYTA trials in adults with major depressive disorder (MDD)1

This image shows a bar labeled Mild, Moderate, and Severe with a marker placed near the Severe end of the scale.

Patients had moderate to
severe depression1
Mean baseline MADRS total scores for CAPLYTA patients: 30.4 in Study 501, and 30.8 in Study 502. Scores were similar for the placebo + antidepressant group (30.1 and 31.5, respectively).

  • 100%of patients had moderate
    to severe depressive symptoms1,2
  • ~90%of patients had inadequate response to 1 prior antidepressant therapy in the current episode2
  • 41%of patients had symptoms of anxiety* at baseline2

*CAPLYTA is not approved for the treatment of anxiety disorders. Symptoms of anxiety in patients with MDD are based on DSM-5 criteria for anxious distress.

Studies 501 (N=485) and 502 (N=480) were global, multicenter, randomized, double-blind, placebo-controlled trials1,4,5

  • Screening phaseUp to 2 weeks

    • Patients were 18-65 years old1
    • Met DSM-5 criteria and had1:
      • Inadequate response (<50% improvement to 1-2 courses of antidepressant therapy)1
      • Moderate to severe
        depressive symptoms (MADRS ≥24)4,5

  • Treatment phase6 weeks

    Oral CAPLYTA 42 mg
    (without titration) +
    an antidepressant

    Placebo + an antidepressant

  • Follow up phase1 week

    Safety Follow-Up

At 6 weeks, there was a significant symptom relief with a placebo-subtracted difference of -4.9 points in Study 501 and -4.5 points in Study 502.1 A ≥2-point difference from placebo is considered clinically meaningful.6

The primary efficacy measure was mean change in MADRS total score at 6 weeks1

Baseline antidepressant treatments

Enrolled patients were taking common antidepressants, including2:

SSRI

  • Citalopram
  • Escitalopram
  • Sertraline
  • Paroxetine
  • Fluoxetine
  • Vortioxetine
  • Vilazodone

SNRI

  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine
  • Levomilnacipran
  • Milnacipran (where locally approved)

Other

  • Bupropion

Full graph description

These graphs depict the change from baseline in MADRS total score in two pivotal studies over 6 weeks, for adult patients receiving CAPLYTA 42 mg or placebo as adjunctive therapy with an antidepressant.2

In Study 501, patients on CAPLYTA saw a 14.7-point reduction at 6 weeks compared to a 9.8-point reduction with placebo (placebo-subtracted difference of -4.9; P<0.0001). In Study 502, patients on CAPLYTA saw a 14.7-point reduction at 6 weeks compared to 10.2-point reduction with placebo (placebo-subtracted difference of 4.5; P<0.0001).2

MADRS is a validated rating scale used in clinical trials to support an MDD indication by the FDA1,7-10

The MADRS total score ranges from 0 to 60. Higher scores reflect greater symptom severity. Each item is rated to assess depression severity and/or monitor response to antidepressant medication.

Symptom severity score

Each item on this 10-item scale is scored from 0 to 6, with 0 being the least severe and 6 being most severe

  1. Reported Sadness
  2. Apparent Sadness
  1. Concentration Difficulties
  2. Lassitude
  1. Inability to Feel
  2. Inner Tension (Anxiety)
  1. Reduced Sleep
  2. Reduced Appetite
  1. Pessimistic Thoughts
  2. Suicidal Thoughts

The total score ranges from 0 to 60

This image shows a horizontal scale divided into four ranges: Normal (0-6), Mild (7-19), Moderate (20-34), and Severe (35-60).

DSM=Diagnostic and Statistical Manual of Mental Disorders; MADRS=Montgomery-Åsberg Depression Rating Scale; MDD=major depressive disorder; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor.

See pooled results for MADRS individual items
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Indications

CAPLYTA is indicated in adults for adjunctive therapy along with antidepressants for the treatment of major depressive disorder (MDD); the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate; and the treatment of schizophrenia.

Important Safety Information

BOXED WARNINGS:

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis.
  • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA have not been established in pediatric patients.

Contraindications: CAPLYTA is contraindicated in patients with a history of hypersensitivity to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g., allergic dermatitis, papular rash, and generalized rash), and urticaria.

Warnings & Precautions: Antipsychotic drugs have been reported to cause:

  • Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke and transient ischemic attack. See Boxed WARNING above.
  • Neuroleptic Malignant Syndrome, which is a potentially fatal reaction. Signs and symptoms include hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Manage with immediate discontinuation of CAPLYTA and provide intensive symptomatic treatment and monitoring.
  • Tardive Dyskinesia (TD) may develop in patients treated with antipsychotic drugs, including CAPLYTA. TD can develop after a relatively brief treatment period, even at low doses, or after treatment discontinuation. The TD risk appears to be highest in elderly women. The likelihood that TD will become irreversible increases with the duration of the antipsychotic drug treatment and cumulative dose. If signs and symptoms of TD appear, consider discontinuing CAPLYTA if clinically appropriate.
  • Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. Measure weight and assess fasting plasma glucose and lipids when initiating CAPLYTA and monitor periodically during long-term treatment.
  • Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases). Perform complete blood counts in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing CAPLYTA if clinically significant decline in WBC occurs in absence of other causative factors. Discontinue CAPLYTA in patients with clinically significant neutropenia or absolute neutrophil count <1000/mm3 and monitor closely until neutropenia resolves.
  • Orthostatic Hypotension and Syncope. Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension.
  • Falls. CAPLYTA may cause somnolence, postural hypotension, and motor and/or sensory instability, which may lead to falls and, consequently, fractures and other injuries. Assess patients for fall risk when initiating treatment and periodically during long-term treatment.
  • Seizures. Use CAPLYTA cautiously in patients with a history of seizures or with conditions that lower seizure threshold.
  • Potential for Cognitive and Motor Impairment. Advise patients to use caution when operating machinery or motor vehicles until they know how CAPLYTA affects them.
  • Body Temperature Dysregulation. Use CAPLYTA with caution in patients who may experience conditions that may increase core body temperature such as strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics.
  • Dysphagia. Use CAPLYTA with caution in patients at risk for aspiration.

Drug Interactions:

  • Avoid concomitant use with CYP3A4 inducers.
  • Reduce dose for concomitant use with strong CYP3A4 inhibitors (10.5 mg) or moderate CYP3A4 inhibitors (21 mg).
  • Increased monitoring for serotonin reuptake inhibitor (SRI)‑associated adverse reactions is recommended when used with SRIs; including in geriatric patients who may be at greater risk for clinically significant hyponatremia.

Special Populations: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Reduce dose for patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment (21 mg).

Adverse Reactions: The most common adverse reactions in clinical trials (≥5% and greater than twice placebo) with CAPLYTA vs placebo were:

  • Major Depressive Disorder (Adjunctive therapy): dizziness (17% vs 5%), dry mouth (13% vs 3%), somnolence/sedation (12% vs 2%), nausea (9% vs 4%), fatigue (8% vs 2%), and diarrhea (5% vs 1%).
  • Bipolar Depression (Monotherapy, Adjunctive therapy): somnolence/sedation (13% vs 3%, 13% vs 3%), dizziness (8% vs 4%, 11% vs 2%), nausea (8% vs 3%, 9% vs 4%), and dry mouth (5% vs 1%, 5% vs 1%).
  • Schizophrenia: somnolence/sedation (24% vs 10%) and dry mouth (6% vs 2%).

CAPLYTA is available in 42 mg, 21 mg, and 10.5 mg capsules.

Indications

CAPLYTA is indicated in adults for adjunctive therapy along with antidepressants for the treatment of major depressive disorder (MDD); the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate; and the treatment of schizophrenia.

US‑CAP‑2500828

Please see full Prescribing Information, including Boxed WARNINGS.

References: 1. CAPLYTA Prescribing Information. 2. Data on File (REF-02960). 3. Hawley CJ, Gale TM, Smith PSJ, et al. Equations for converting scores between depression scales (MADRS, SRS, PHQ‑9 and BDI‑II): good statistical, but weak idiographic, validity. Hum psychopharmacol. 2013;28(6):544–551. doi:10.1002/hup.2341 4. Clinical trial of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov. identifier: NCT04985942 Updated May 2, 2025. Accessed June 25, 2025. https://clinicaltrials.gov/study/NCT04985942 5. Multicenter study of lumateperone as adjunctive therapy in the treatment of patients with major depressive disorder. ClinicalTrials.gov identifier: NCT05061706 Updated May 5, 2025. Accessed July 17, 2025. https://clinicaltrials.gov/study/NCT05061706 6. Montgomery SA, Moller HJ. Is the significant superiority of escitalopram compared with other antidepressants clinically relevant? Int Clin Psychopharmacol. 2009;24(3):111‑118. doi:10.1097/YIC.0b013e32832a8eb2 7. Hengartner MP, Jakobsen JC, Sorensen A, Ploderl M. Efficacy of new‑generation antidepressants assessed with the Montgomery‑Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta‑analysis of randomised placebo‑controlled trials. PLoS One. 2020;15(2):e0229381. doi:10.1371/journal.pone.0229381 8. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382‑389. doi:10.1192/bjp.134.4.382 9. Quilty LC, Robinson JJ, Rolland JP, Fruyt FD, Rouillon F, Bagby RM. The structure of the Montgomery‑Asberg depression rating scale over the course of treatment for depression. Int J Methods Psychiatr Res. 2013;22(3):175‑184. doi:10.1002/mpr.1388 10. Thase ME, Harrington A, Calabrese J, Montgomery S, Niu X, Patel MD. Evaluation of MADRS severity thresholds in patients with bipolar depression. J Affect Disord. 2021;286:58‑63. doi:10.1016/j.jad.2021.02.043

BOXED WARNINGS:

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis.
  • Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA have not been established in pediatric patients.